sRAGE alleviates neutrophilic asthma by blocking HMGB1/RAGE signalling in airway dendritic cells

Zhang, Fang; Su, Xin; Huang, Gang; X, Xin; Cao, E-Hong; Shi, Yi; Song, Yong

doi:10.1038/s41598-017-14667-4

Cited by 51 publications

(43 citation statements)

References 49 publications

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“…HMGB1 can recruit and activate DCs and instruct DCs to trigger T H 2 responses following HDM sensitization. 4,24,32 Thus, the elevated levels of extracellular HMGB1 after HDM exposure in Pag1 −/− mice may be responsible for the increased recruitment of MoDCs to the lung and mLNs. As an innate source of type 2 cytokines, ILC2s also facilitate the differentiation of CD4 + T cells to T H 2 cells.…”

Section: Discussionmentioning

confidence: 99%

PAG1 limits allergen‐induced type 2 inflammation in the murine lung

Ullah

Vicente

Collinson

et al. 2019

Allergy

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Background Phosphoprotein associated with glycosphingolipid‐enriched microdomains 1 (PAG1) is a transmembrane adaptor protein that affects immune receptor signaling in T and B cells. Evidence from genome‐wide association studies of asthma suggests that genetic variants that regulate the expression of PAG1 are associated with asthma risk. However, it is not known whether PAG1 expression is causally related to asthma pathophysiology. Here, we investigated the role of PAG1 in a preclinical mouse model of house dust mite (HDM)‐induced allergic sensitization and allergic airway inflammation. Methods Pag1‐deficient (Pag1−/−) and wild‐type (WT) mice were sensitized or sensitized/challenged to HDM, and hallmark features of allergic inflammation were assessed. The contribution of T cells was assessed through depletion (anti‐CD4 antibody) and adoptive transfer studies. Results Type 2 inflammation (eosinophilia, eotaxin‐2 expression, IL‐4/IL‐5/IL‐13 production, mucus production) in the airways and lungs was significantly increased in HDM sensitized/challenged Pag1−/− mice compared to WT mice. The predisposition to allergic sensitization was associated with increased airway epithelial high‐mobility group box 1 (HMGB1) translocation and release, increased type 2 innate lymphoid cells (ILC2s) and monocyte‐derived dendritic cell numbers in the mediastinal lymph nodes, and increased T‐helper type 2 (TH2)‐cell differentiation. CD4+ T‐cell depletion studies or the adoptive transfer of WT OVA‐specific CD4+ T cells to WT or Pag1−/− recipients demonstrated that the heightened propensity for TH2‐cell differentiation was both T cell intrinsic and extrinsic. Conclusion PAG1 deficiency increased airway epithelial activation, ILC2 expansion, and TH2 differentiation. As a consequence, PAG1 deficiency predisposed toward allergic sensitization and increased the severity of experimental asthma.

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Section: Discussionmentioning

confidence: 99%

PAG1 limits allergen‐induced type 2 inflammation in the murine lung

Ullah

Vicente

Collinson

et al. 2019

Allergy

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“…AAV9 is widely used in the research of respiratory for it is one of the most e cient serotypes to infect lung epithelium cells. Studies have reported that sRAGE reduced the neutrophil in ltration of lung tissue in LPS-induced acute lung injury mouse model [15] and the airway neutrophil in ammation in asthmatic mice [16]. Consistent with the existing research, overexpressed sRAGE not only signi cantly reduced the in ltration of in ammatory cells and in ammation score of lung tissue in NA mice but also sharply inhibited the in ammatory cells and neutrophils in BALF, which implying that sRAGE de ciency may participate in airway neutrophilic in ammation of NA mice.…”

Section: Discussionmentioning

confidence: 99%

“…However, AAV9-sRAGE restored the expressions of E-cadherin and Vimentin, implying that sRAGE overexpression may reduce airway EMT in NA mice. A study has revealed that sRAGE alleviated the Th17 cell response and airway neutrophilic in ammation in NA mice through competing with a RAGE ligand -HMGB1 [16]. RAGE was highly expressed in the lung tissues of asthmatic mice and was involved in the mucus hypersecretion and airway remodeling of asthma [31].…”

Section: Discussionmentioning

confidence: 99%

Soluble advanced glycosylation receptor is a potential target for the treatment of neutrophilic asthma

Zhang¹,

Xie²,

Sun³

et al. 2020

Preprint

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Background Neutrophilic asthma (NA) was a subtype of asthma. Soluble advanced glycosylation receptor (sRAGE) was considered to be associated with the neutrophilic airway. However, the role of sRAGE in NA still limited. Methods A NA mouse model was established and the levels of sRAGE in the bronchoalveolar lavage fluid (BALF) were measured by ELISA. Hematoxylin-eosin (HE) and Masson trichrome staining were used to identifying airway remodeling. Adeno-associated virus 9 (AAV9) overexpressed sRAGE and inhibitors for HMGB1, RAGE, and PI3K were used to intervene NA mouse model via tail-vein injection and intraperitoneally injection. Expressions of airway remodeling, EMT, and signaling markers were detected using qRT-PCR or western blotting. The levels of IL-17 and IL-6 in BALF were measured by ELISA. HMGB1 was applied to induce EMT of human bronchial epithelial cells (16HBE), then E-cadherin and vimentin expressions were examined after sRAGE, RAGE inhibitor, and PI3K inhibitor administration. Results sRAGE levels were significantly reduced in BALF and the airway remodeling was observed in the NA mouse model. AAV9-sRAGE significantly inhibited the neutrophilic airway inflammation, airway remodeling, and the expression of IL-17, IL-6, TGF-β1, RAGE, PI3K, and EMT markers -E-cadherin and vimentin in vivo. HMGB1 inhibitor, RAGE inhibitor, and PI3K inhibitor upregulated E-cadherin level. Moreover, HMGB1 promoted the EMT process via RAGE/PI3K in 16HBE cells and sRAGE reversed HMGB1- induced EMT in vitro. Conclusion sRAGE levels decrease in the mouse model with NA. sRAGE treatment attenuates neutrophilic airway inflammation, airway remodeling, and EMT. This suggests sRAGE may yield benefits in the treatment of NA.

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“…Interaction of RAGE with these ligands leads to activation of inflammatory responses, induction of oxidative stress and tissue remodeling responses. Soluble form of receptor for advanced glycation end‐products serves as a decoy receptor by sequestering RAGE ligands and thus inhibiting RAGE dependent cellular responses . However, further studies are needed to determine whether deficiency in sRAGE is a causative factor for airway neutrophilia or rather a result of neutrophilic inflammation (degradation due to excessive levels of neutrophil‐derived enzymes).…”

Section: Endotypes and Underlying Mechanisms Of Non‐t2 Asthmamentioning

confidence: 99%

Mechanisms and therapeutic strategies for non‐T2 asthma

Sze

Bhalla

Nair

2019

Allergy

191

169

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Non‐T2 asthma is traditionally defined as asthma without features of T2 asthma. The definition is arbitrary and is generally based on the presence of neutrophils in sputum, or the absence (or normal levels) of eosinophils or other T2 markers in sputum (paucigranulocytic), airway biopsies or in blood. This definition may be imprecise as we gain more knowledge from applying transcriptomics and proteomics to blood and airway samples. The prevalence of non‐T2 asthma is also difficult to estimate as most studies are cross‐sectional and influenced by concomitant treatment with glucocorticosteroids, and by the presence of recognized or unrecognized airway infections. No specific therapies have shown any clinical benefits in patients with asthma that is associated with a non‐T2 inflammatory process. It remains to be seen if such an endotype truly exists and to identify treatments to target that endotype. Meanwhile, identifying intense airway neutrophilia as an indicator of airway infection and airway hyperresponsiveness as an indicator of smooth muscle dysfunction, and treating them appropriately, and not increasing glucocorticosteroids in patients who do not have obvious T2 inflammation, seem reasonable.

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sRAGE alleviates neutrophilic asthma by blocking HMGB1/RAGE signalling in airway dendritic cells

Cited by 51 publications

References 49 publications

PAG1 limits allergen‐induced type 2 inflammation in the murine lung

PAG1 limits allergen‐induced type 2 inflammation in the murine lung

Soluble advanced glycosylation receptor is a potential target for the treatment of neutrophilic asthma

Mechanisms and therapeutic strategies for non‐T2 asthma

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